Hundreds of medically useful compounds are discovered each year, but clinical use of these drugs is possible only if a drug delivery vehicle is developed to transport them to their therapeutic target in the human body. This problem is particularly critical for drugs requiring intravenous injection in order to reach their therapeutic target or dosage but which are water insoluble or poorly water soluble. For such hydrophobic compounds, direct injection may be impossible or highly dangerous, and can result in hemolysis, phlebitis, hypersensitivity, organ failure and/or death. Such compounds are termed by pharmacists “lipophilic”, “hydrophobic”, or in their most difficult form, “amphiphobic”.
A few examples of therapeutic substances in these categories are ibuprofen, diazepam, griseofulvin, cyclosporin, cortisone, proleukin, etoposide and paclitaxel. Kagkadis, K A et al. (1996) PDA J Pharm Sci Tech 50(5):317–323; Dardel, O. 1976. Anaesth Scand 20:221–24. Sweetana, S and M J U Akers. (1996) PDA J Pharm Sci Tech 50(5):330–342.
Administration of chemotherapeutic or anti-cancer agents is particularly problematic. The majority of these agents are poorly soluble and thus are difficult to deliver in aqueous solvents and supply at therapeutically useful levels. On the other hand, water-soluble anti-cancer agents are generally taken up by both cancer and non-cancer cells, thereby exhibiting non-specificity.
Efforts to improve water-solubility and comfort of administration of such agents have not solved, and may have worsened, the two fundamental problems of cancer chemotherapy: 1) non-specific toxicity and 2) rapid clearance form the bloodstream by non-specific mechanisms. In the case of cytotoxins, which form the majority of currently available chemotherapies, these two problems are clearly related. Whenever the therapeutic is taken up by non-cancerous cells, a diminished amount of the drug remains available to treat the cancer, and more importantly, the normal cell ingesting the drug is killed.
To be effective in treating cancer, the chemotherapeutic must be present throughout the affected tissue(s) at high concentration for a sustained period of time so that it may be taken up by the cancer cells, but not at so high a concentration that normal cells are injured beyond repair. Obviously, water soluble molecules can be administered in this way, but only by slow, continuous infusion and monitoring, aspects which entail great difficulty, expense and inconvenience.
A more effective method of administering a cancer therapeutic, particularly a cytotoxin, is in the form of a dispersion of oil in which the drug is dissolved. These oily particles are made electrically neutral and coated in such a way that they do not interact with plasma proteins and are not trapped by the reticuloendothelial system (RES), instead remaining intact in the tissue or blood for hours, days or even weeks. It is desirable when the particles also distribute themselves into the surrounding lymph nodes which are injected at the site of a cancer. Nakamoto, Y et al. (1975) Chem Pharm Bull 23(10):2232–2238. Takahashi, T et al. (1977) Tohoku J Exp Med 123:235–246. In many cases direct injection into blood is the route of choice for administration. Even more preferable, following intravenous injection, the blood-borne particles may be preferentially captured and ingested by the cancer cells themselves. An added advantage of a particulate emulsion for the delivery of a chemotherapeutic is the widespread property of surfactants used in emulsions to overcome multidrug resistance.
For drugs that cannot be formulated as an aqueous solution, emulsions have typically been most cost-effective and gentle to administer, although there have been serious problems with making them sterile and endotoxin free so that they may be administered by intravenous injection. The oils typically used for pharmaceutical emulsions include saponifiable oils from the family of triglycerides, for example, soybean oil, sesame seed oil, cottonseed oil, safflower oil and the like. Hansrani, P K et al., (1983) J. Parenter Sci. Technol 37:145–150. One or more surfactants are used to stabilize the emulsion, and excipients are added to render the emulsion more biocompatible, stable and less toxic. Lecithin from egg yolks or soybeans is a commonly used surfactant. Sterile manufacturing can be accomplished by absolute sterilization of all the components before manufacture, followed by absolutely aseptic technique in all stages of manufacture. However, improved ease of manufacture and assurance of sterility is obtained by terminal sterilization following sanitary manufacture, either by heat or by filtration. Unfortunately, not all emulsions are suitable for heat or filtration treatments.
Stability has been shown to be influenced by the size and homogeneity of the emulsion. The preferred emulsion consists of a suspension of sub-micron particles, with a mean droplet diameter of no greater than 200 nanometers. A stable dispersion in this size range is not easily achieved, but has the benefit that it is expected to circulate longer in the bloodstream. Further, less of the stable dispersion in this size range is phagocytized non-specifically by the reticuloendothelial system. As a result the drug is more likely to reach its therapeutic target. Thus, a preferred drug emulsion will be designed to be actively taken up by the target cell or organ, and is targeted away from the RES.
The use of vitamin E in emulsions is known. In addition to the hundreds of examples where vitamin E in small quantities (for example, less than 1%, Lyons, R. T., Pharm Res 13(9): S-226, (1996) “Formulation development of an injectable oil-in-water emulsion containing the lipophilic antioxidants α-tocopherol and β-carotene”) is used as an anti-oxidant in emulsions, the first primitive, injectable vitamin E emulsions per se were made by Hidiroglou for dietary supplementation in sheep and for research on the pharmacokinetics of vitamin E and its derivatives. Hidiroglou M. and Karpinski K. (1988) Brit J Nutrit 59:509–518.
For mice, an injectable form of vitamin E was prepared by Kato and coworkers. Kato Y., et al. (1993) Chem Pharm Bull 41(3):599–604. Micellar solutions were formulated with Tween 80, Brij 58 and HCO-60. Isopropanol was used as a co-solvent, and was then removed by vacuum evaporation; the residual oil glass was then taken up in water with vortexing as a micellar suspension. An emulsion was also prepared by dissolving vitamin E with soy phosphatidycholine (lecithin) and soybean oil. Water was added and the emulsion prepared with sonication.
In 1983, E-Ferol, a vitamin B emulsions was introduced for vitamin E supplementation and therapy in neonates. Alade, S. L., et al. (1986) Pediatrics 77(4):593–597. Within a few months over 30 babies had died as a result of receiving the product, and the product was promptly withdrawn by FDA order. The surfactant mixture used in E-Ferol to emulsify 25 mg/mL vitamin E consisted of 9% Tween 80 and 1% Tween 20. These surfactants at the employed levels seem ultimately to have been responsible for the unfortunate deaths. This experience illustrates the need for improved formulations and the importance of selecting suitable biocompatible surfactants and carefully monitoring their levels in parenteral emulsions.
An alternative means of solubilizing low solubility compounds is direct solubilization in a non-aqueous milieu, for examples alcohol (such as ethanol) dimethylsulfoxide or triacetin. An example in PCT application WO 95/11039 describes the use of vitamin E and the vitamin E derivative TPGS in combination with ethanol and the immuno-suppressant molecule cyclosporin. U.S. Pat. No. 5,689,846 discloses various alcohol solutions of paclitaxel. U.S. Pat. No. 5,573,781 discloses the dissolution of paclitaxel in ethanol, butanol and hexanol and an increase in the antitumor activity of paclitaxel when delivered in butanol and hexanol as compared to ethanol. Alcohol-containing solutions can be administered with care, but are typically given by intravenous drip to avoid the pain, vascular irritation and toxicity associated with bolus injection of these solutions.
PCT publication WO 95/21217 (Dumex Ltd) discloses that tocopherols can be used as solvents and/or emulsifiers of drugs that are substantially insoluble in water, in particular for the preparation of topical formulations. The use of vitamin E-TPGS as an emulsifier in formulations containing high levels of α-tocopherol is mentioned in the specification (pages 7–8 and 12). Examples 1 to 5 disclose formulations for topical administration comprising a lipid layer (α-tocopherol), the drug and vitamin E-TPGS, in quantities of less than 25% w/w of the formulation, as an emulsifier. WO95/2 1217 does not suggest or describe anticancer agents or taxanes.
PCT Publication WO 97/03651 (Danbiosyst UK Ltd.) discloses lipid vehicle drug delivery compositions that contain at least five ingredients: a therapeutic drug, vitamin E, an oil in which the drug and vitamin E are dissolved, a stabilizer (either phospholipid, a lecithin, or a poloxamer which is a polyoxyethylene-polyoxypropylene copolymer) and water. The therapeutic drugs disclosed are itraconazole and paclitaxel. The “therapeutic emulsion” compositions require two oils in the dispersed phase where the therapeutic drug resides, vitamin E and another oil, typically a triglyceride such as soybean oil. The only working example with paclitaxel, Example 16, also contains both vitamin E and soybean oil.
N-methyl-2-pyrrolidone (NMP), under the trade name Pharmosolve™, can be used to improve the solubility of poorly soluble drugs in pharmaceutical formulations and has appeared in recent literature for use in veterinary medicine with forthcoming application in humans. Furthermore, polyvinylpyrrolidone (PVP) under the trade name Povidone™ with a molecular weight between 2,500 to 100,000 at a concentration of 1 to 5 percent (w/v) of the aqueous injectable base can be used as a co-solubilizer along with NMP. U.S. Pat. No. 5,726,181 discloses antitumor compositions and suspensions comprising NMP and highly lipophilic camptothecin derivatives.
Polyethylene glycols (PEGs) and PVP are examples of two water-soluble polymers frequently used to modify the solubility behavior of drugs, including paclitaxel. Although the solubility of paclitaxel in both solvents is relatively high, in dilute aqueous solutions that are suitable for parenteral administration the solubility of the drug is low and the potential for drug precipitation upon dilution is high. In admixtures of PEG 400 and water containing 50–100% PEG 400, the solubility of paclitaxel varies from 0.2 to 175 mg/ml, respectively. Thus, paclitaxel solubilities are quite low where larger amounts of water are used, e.g., solubilities in 35% PEG 400 and 30% PVP in water are 0.03 mg/ml and ≦0.3 mg/ml, respectively. “Solubility of Paclitaxel in Polyethylene Glycol 400/Water Mixtures” Straubinger, R. M., Biopharmaceutics of Paclitaxel (Taxol): Formulation. Activity and Pharmacokinetics (p. 244), in: Taxol: Science and Applications, (M. Suffness, ed.), CRC Press, Boca Raton, 1995). The use of PEG-400 is not limited to paclitaxel and can be applied to other therapeutic agents which exhibit good solubility in polyethylene glycols (for example, Etoposide). Derivative forms of paclitaxel including polyethylene glycol derivatives are described in U.S. Pat. No. 5,614,549.
In addition to poor solubility and the potential for drug precipitation with pharmaceutical formulations in non-aqueous solvents such as alcohol (ethanol, isopropanol, benzyl alcohol, etc.) along with surfactants, another problem is the ability of these solvents to extract toxic substances, for examples plasticizers, from their containers. The current commercial formulation for the anti-cancer drug paclitaxel, for example, consists of a mixture of hydroxylated castor oil and ethanol, and rapidly extracts plasticizers such as di-(2-ethylhexyl)-phthalate from commonly used intravenous infusion tubings and bags. Adverse reactions to the plasticizers have been reported, such as respiratory distress, necessitating the use of special infusion systems at extra expense and time. Waugh, W. N., et al. (1991) Am. J. Hosp. Pharmacists 48:1520.
In light of these problems, it can be seen that the ideal emulsion vehicle would be inexpensive, non-irritating or even nutritive and palliative in itself, terminally sterilizable by either heat or filtration, stable for at least 1 year under controlled storage conditions, accommodate a wide variety of water insoluble and poorly soluble drugs and be substantially ethanol-free. In addition to those drugs which are lipophilic and dissolve in oils, also needed is a vehicle which will stabilize, and carry in the form of an emulsion, drugs which are poorly soluble in lipids and in water.